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ACS Omega DOI:10.1021/acsomega.2c00541

High-Throughput Assay to Screen Small Molecules for Their Ability to Prevent Sickling of Red Blood Cells.

Publication TypeJournal Article
Year of Publication2022
AuthorsNakagawa, A, Cooper, MK, Kost-Alimova, M, Berstler, J, Yu, B, Berra, L, Klings, ES, Huang, MS, Heeney, MM, Bloch, DB, Zapol, WM
JournalACS Omega
Volume7
Issue16
Pages14009-14016
Date Published2022 Apr 26
ISSN2470-1343
Abstract

Sickle cell disease (SCD) is an inherited disorder of hemoglobin (Hb); approximately 300,000 babies are born worldwide with SCD each year. In SCD, fibers of polymerized sickle Hb (HbS) form in red blood cells (RBCs), which cause RBCs to develop their characteristic "sickled" shape, resulting in hemolytic anemia and numerous vascular complications including vaso-occlusive crises. The development of novel antisickling compounds will provide new therapeutic options for patients with SCD. We developed a high-throughput "sickling assay" that is based on an automated high-content imaging system to quantify the effects of hypoxia on the shape and size of RBCs from HbSS SCD patients (SS RBCs). We used this assay to screen thousands of compounds for their ability to inhibit sickling. In the assay, voxelotor (an FDA-approved medication used to treat SCD) prevented sickling with a '-factor > 0.4, suggesting that the assay is capable of identifying compounds that inhibit sickling. We screened the Broad Repurposing Library of 5393 compounds for their ability to prevent sickling in 4% oxygen/96% nitrogen. We identified two compounds, SNS-314 mesylate and voxelotor itself, that successfully prevented sickling. SNS-314 mesylate prevented sickling in the absence of oxygen, while voxelotor did not, suggesting that SNS-314 mesylate acts by a mechanism that is different from that of voxelotor. The sickling assay described in this study will permit the identification of additional, novel antisickling compounds, which will potentially expand the therapeutic options for SCD.

DOI10.1021/acsomega.2c00541
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/35559170?dopt=Abstract

Alternate JournalACS Omega
PubMed ID35559170
PubMed Central IDPMC9089379